Background/Aims: Five somatostatin receptors subtypes (SSTR) have been characterized in the gastrointestinal tract.Both bioactive forms of somatostatin, S-14 and S-28, bind to all SSTR's, but S-28 localized predominantly in ileum/colon has preferential affinity for SSTR5.This study examined whether SSTR-5 mediates somatostatin inhibition of PYY, also found in ileum/colon.Methods: Rat intestinal cultures were treated with somatostatin agonists with relatively high specificity for SSTR1-5.Results: Administration of GRP (10-TM) stimulated PYY secretion to 161 _+ 12% of paired controls; this response was not influenced by pertussis toxin (200 ng/ml) or nitredipine (50 uM).PYY secretion was more potently inhibited by S-28 (ICso 0.1nM) then by S-14 (IC5o 100nM).Phosphoramidon and amastatin did not alter the potencies of S-28 or S-14.The SSTR5 agonist, BIM 23052 inhibited PYY secretion (ICs0 0.1nM) with similar potency to S-28.Whereas the SSTR5 agonist L372, 588 also inhibited PYY (IC5o 0.1nM), the structurally-related peptides L-372, 587 (tyrosine conversion: 7 from 2) and L362, 855 (phenylalanines: both 2 and 7) caused no inhibition at I00 nM.The SSTR agonist NC8-12 was marginally more potent (ICso 50nM) than S-14 while an SSTR3 agonist was without effect at 100nM.Pertussis toxin blocked PYY inhibition by S-28 and the SSTR5 agonists; nitredipine was without effect.PYY stimulated by PMA was abolished by S-28 and the SSTR-5 agonists at lnM, but after forskolin-stimulated PYY secretion, S-28 and BIM 23052 caused two-fold less inhibition and L372,588 was without effect.Conclusions: S-28, acting through a G i protein mediates inhibition of GRP and protein-kinase C stimulated PYY secretion through SSTR5 activation.Hydroxyl group conversions of SSTR5 peptides may facilitate the development of more potent agonists or antagonists.